Abstract LB-3: Apolipoprotein (E) is a determinant of colon carcinogenesis potentially by regulating inflammation and β-catenin independently of its role in lipid metabolism

Abstract

Abstract Colorectal cancer is a leading cause of cancer-related mortality. Apolipoprotein E (ApoE) is a major player in cholesterol metabolism and has been suggested, through association studies, to play a role in colon homoeostasis and cancer. Genetic studies suggested that polymorphisms in the ApoE alleles constitute a risk factor for the development of colon cancer. Collectively, these studies explored the role of ApoE in colon cancer by narrowly focusing on its established function in lipid metabolism. In the current study, we utilized a genetic mouse model (ApcMin mouse) of colon cancer to test the hypothesis that ApoE is a determinant in the disease progression. We show that ApoE gene heterozygosity, which reduces the protein (∼50%) and minimally affects the lipid profile, significantly increased tumor burden in ApcMin mice both in the small intestine and the colon. Surprisingly, ApoE gene knockout, which completely eliminates the protein and drastically elevates the lipid profile, did not aggravate the tumor burden in ApcMin mice compared to that caused by gene heterozygosity, suggesting a novel and cholesterol-metabolism-independent function for ApoE in colon homeostasis. In vitro studies with primary colon epithelial cells, isolated using a novel technique developed by our laboratory, show that ApoE-deficiency achieved by ApoE heterozygosity, knockout, or knockdown increased the level of active β-catenin in the absence of any stimulation. It appears that such increase in β-catenin may be at an mRNA level. ApoE deficiency was also associated with an increase in inflammatory factors including VCAM-1, MCP-1, and COX-2 in TNF-treated colon epithelial cells. Altogether, our preliminary results suggest a major role of ApoE in colon homeostasis and that deficiency in ApoE levels may constitute a risk factor for colon cancer progression. Citation Format: Ali I. Elbahrawy, Abdelmetalab Tarhuni, Amarjit S. Naura, Youssef Errami, Mohamed Alwan, Samar Hammad, Jimena Trillo-Tinoco, Ramadan Hemeida, Hassan Brim, Hassan Ashktorab, Luis Del Valle, Hamid A. Boulares. Apolipoprotein (E) is a determinant of colon carcinogenesis potentially by regulating inflammation and β-catenin independently of its role in lipid metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-3. doi:10.1158/1538-7445.AM2014-LB-3